scholarly journals Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

2010 ◽  
Vol 299 (4) ◽  
pp. H1262-H1264 ◽  
Author(s):  
Carmen Methner ◽  
Katharina Schmidt ◽  
Michael V. Cohen ◽  
James M. Downey ◽  
Thomas Krieg
Keyword(s):  
Infarct Size ◽  
Knockout Mice ◽  
Adenosine Receptors ◽  
Coronary Occlusion ◽  
Ischemic Postconditioning ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Cgs 21680 ◽  
Selective Agonists

Pre- and postconditioning depend on the activation of adenosine receptors (ARs) at the end of the index ischemia. The aim of this study was to determine which receptor subtypes must be activated. In situ mouse hearts underwent 30 min of regional ischemia, followed by 2 h of reperfusion. As expected, either ischemic postconditioning (6 cycles of 10 s of reperfusion and 10 s of coronary occlusion) or infusion of the selective A2b adenosine receptor (A2bAR) agonist BAY60-6583 (BAY60) for 60 min, starting 5 min before reperfusion reduced infarct size in wild-type C57Bl/6N mice. Protection from either was abolished by the selective A2bAR antagonist MRS-1754, confirming a role for A2bAR. Additionally, the coadministration of ischemic postconditioning and a selective A2aAR antagonist led to the loss of protection as well. 5′-Ectonucleotidase (CD73) is thought to be necessary for the production of adenosine during ischemia. As predicted, ischemic postconditioning did not protect CD73 knockout mice. Selective agonists of either A2bAR (BAY60) or A2aAR (CGS-21680), as well as the coadministration of ischemic postconditioning and BAY60, also failed to protect hearts of the CD73 knockout mice. But the nonselective A1/A2AR agonist 5′-( N-ethylcarboxamido)adenosine (NECA) was protective, suggesting that the activation of multiple AR subtypes might be required. The coadministration of CGS-21680 and BAY60 also elicited profound protection, indicating that two AR subtypes, A2a and A2b, must be simultaneously activated for protection to occur.

Transgenic overexpression of cardiac A1adenosine receptors mimics ischemic preconditioning

2000 ◽  
Vol 279 (3) ◽  
pp. H1071-H1078 ◽  
Author(s):  
R. Ray Morrison ◽  
Rachael Jones ◽  
Anne M. Byford ◽  
Alyssa R. Stell ◽  
Jason Peart ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Myocardial Function ◽  
Wild Type ◽  
Beneficial Effects ◽  
Pressure Development ◽  
Ldh Release

The role of A1adenosine receptors (A1AR) in ischemic preconditioning was investigated in isolated crystalloid-perfused wild-type and transgenic mouse hearts with increased A1AR. The effect of preconditioning on postischemic myocardial function, lactate dehydrogenase (LDH) release, and infarct size was examined. Functional recovery was greater in transgenic versus wild-type hearts (44.8 ± 3.4% baseline vs. 25.6 ± 1.7%). Preconditioning improved functional recovery in wild-type hearts from 25.6 ± 1.7% to 37.4 ± 2.2% but did not change recovery in transgenic hearts (44.8 ± 3.4% vs. 44.5 ± 3.9%). In isovolumically contracting hearts, pretreatment with selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine attenuated the improved functional recovery in both wild-type preconditioned (74.2 ± 7.3% baseline rate of pressure development over time untreated vs. 29.7 ± 7.3% treated) and transgenic hearts (84.1 ± 12.8% untreated vs. 42.1 ± 6.8% treated). Preconditioning wild-type hearts reduced LDH release (from 7,012 ± 1,451 to 1,691 ± 1,256 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 32.3 ± 11.5%). Preconditioning did not affect LDH release or infarct size in hearts overexpressing A1AR. Compared with wild-type hearts, A1AR overexpression markedly reduced LDH release (from 7,012 ± 1,451 to 917 ± 1,123 U · l−1 · g−1 · min−1) and infarct size (from 62.6 ± 5.1% to 6.5 ± 2.1%). These data demonstrate that murine preconditioning involves endogenous activation of A1AR. The beneficial effects of preconditioning and A1AR overexpression are not additive. Taken with the observation that A1AR blockade equally eliminates the functional protection resulting from both preconditioning and transgenic A1AR overexpression, we conclude that the two interventions affect cardioprotection via common mechanisms or pathways.

Role of A1 adenosine receptors in regulation of vascular tone

2005 ◽  
Vol 288 (3) ◽  
pp. H1411-H1416 ◽  
Author(s):  
Huda E. Tawfik ◽  
J. Schnermann ◽  
Peter J. Oldenburg ◽  
S. Jamal Mustafa
Keyword(s):  
Adenosine Receptors ◽  
Vascular Tone ◽  
Receptor Subtypes ◽  
Vascular Relaxation ◽  
Response Curves ◽  
Cgs 21680 ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Regulation Of Vascular Tone

The vascular response to adenosine and its analogs is mediated by four adenosine receptors (ARs), namely, A1, A2A, A2B, and A3. A2AARs and/or A2BARs are involved in adenosine-mediated vascular relaxation of coronary and aortic beds. However, the role of A1ARs in the regulation of vascular tone is less well substantiated. The aim of this study was to determine the role of A1ARs in adenosine-mediated regulation of vascular tone. A1AR-knockout [A1AR(−/−)] mice and available pharmacological tools were used to elucidate the function of A1ARs and the impact of these receptors on the regulation of vascular tone. Isolated aortic rings from A1AR(−/−) and wild-type [A1AR(+/+)] mice were precontracted with phenylephrine, and concentration-response curves for adenosine and its analogs, 5′- N-ethyl-carboxamidoadenosine (NECA, nonselective), 2-chloro- N6-cyclopentyladenosine (CCPA, A1AR selective), 2-(2-carboxyethyl)phenethyl amino-5′- N-ethylcarboxamido-adenosine (CGS-21680, A2A selective), and 2-chloro- N6-3-iodobenzyladenosine-5′- N-methyluronamide (Cl-IBMECA, A3 selective) were obtained to determine relaxation. Adenosine and NECA (0.1 μM) caused small contractions of 13.9 ± 3.0 and 16.4 ± 6.4%, respectively, and CCPA at 0.1 and 1.0 μM caused contractions of 30.8 ± 4.3 and 28.1 ± 3.9%, respectively, in A1AR(+/+) rings. NECA- and CCPA-induced contractions were eliminated by 100 nM of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, selective A1AR antagonist). Adenosine, NECA, and CGS-21680 produced an increase in maximal relaxation in A1AR(−/−) compared with A1AR(+/+) rings, whereas Cl-IBMECA did not produce contraction in either A1AR(+/+) or A1AR(−/−) rings. CCPA-induced contraction at 1.0 μM was eliminated by the PLC inhibitor U-73122. These data suggest that activation of A1ARs causes contraction of vascular smooth muscle through PLC pathways and negatively modulates the vascular relaxation mediated by other adenosine receptor subtypes.

Mechanisms of Isoflurane-induced Myocardial Preconditioning in Rabbits 

1999 ◽  
Vol 90 (3) ◽  
pp. 812-821 ◽  
Author(s):  
Mohamed S. Ismaeil ◽  
Igor Tkachenko ◽  
Kurt A. Gamperl ◽  
Robert F. Hickey ◽  
Brian A. Cason
Keyword(s):  
At Risk ◽  
Potassium Channels ◽  
Infarct Size ◽  
Adenosine Triphosphate ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Coronary Occlusion ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Isoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways. Methods Myocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance. Results Infarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P<0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant). Conclusions Glyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.

scholarly journals Adenosine Receptors as Targets for Therapeutic Intervention

2014 ◽  
Vol 11 (1) ◽  
pp. 96-101 ◽  
Author(s):  
B Suvarna
Keyword(s):  
Medical Journal ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Receptor Subtypes ◽  
Therapeutic Application ◽  
Chemistry Research ◽  
Wide Range ◽  
The World ◽  
Selective Agonists ◽  
Receptor Modulators

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer. DOI: http://dx.doi.org/10.3126/kumj.v11i1.11054 Kathmandu University Medical Journal Vol.11(1) 2013: 96-101

scholarly journals Role of Caveolin-3 and Glucose Transporter-4 in Isoflurane-induced Delayed Cardiac Protection

2010 ◽  
Vol 112 (5) ◽  
pp. 1136-1145 ◽  
Author(s):  
Yasuo M. Tsutsumi ◽  
Yoshitaka Kawaraguchi ◽  
Yousuke T. Horikawa ◽  
Ingrid R. Niesman ◽  
Michael W. Kidd ◽  
...  
Keyword(s):  
Infarct Size ◽  
Knockout Mice ◽  
Glucose Transporter ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Transporter 4 ◽  
Wild Type ◽  
Cardiac Protection ◽  
Caveolin 1 ◽  
Discontinuous Sucrose Gradient

Background Caveolae are small, flask-like invaginations of the plasma membrane. Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling. The authors tested the hypothesis that delayed cardiac protection induced by volatile anesthetics is caveolae or caveolin dependent. Methods An in vivo mouse model of ischemia-reperfusion injury with delayed anesthetic preconditioning (APC) was tested in wild-type, caveolin-1 knockout, and caveolin-3 knockout mice. Mice were exposed to 30 min of oxygen or isoflurane and allowed to recover for 24 h. After 24 h recovery, mice underwent 30-min coronary artery occlusion followed by 2 h of reperfusion at which time infarct size was determined. Biochemical assays were also performed in excised hearts. Results Infarct size as a percent of the area at risk was reduced by isoflurane in wild-type (24.0 +/- 8.8% vs. 45.1 +/- 10.1%) and caveolin-1 knockout mice (27.2 +/- 12.5%). Caveolin-3 knockout mice did not show delayed APC (41.5 +/- 5.0%). Microscopically distinct caveolae were observed in wild-type and caveolin-1 knockout mice but not in caveolin-3 knockout mice. Delayed APC increased the amount of caveolin-3 protein but not caveolin-1 protein in discontinuous sucrose-gradient buoyant fractions. In addition, glucose transporter-4 was increased in buoyant fractions, and caveolin-3/glucose transporter-4 colocalization was observed in wild-type and caveolin-1 knockout mice after APC. Conclusions These results show that delayed APC involves translocation of caveolin-3 and glucose transporter-4 to caveolae, resulting in delayed protection in the myocardium.

scholarly journals CRYAB and HSPB2 deficiency alters cardiac metabolism and paradoxically confers protection against myocardial ischemia in aging mice

2007 ◽  
Vol 293 (5) ◽  
pp. H3201-H3209 ◽  
Author(s):  
Ivor J. Benjamin ◽  
Yiru Guo ◽  
Sathyanarayanan Srinivasan ◽  
Sihem Boudina ◽  
Ryan P. Taylor ◽  
...  
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Ex Vivo ◽  
Double Knockout ◽  
Area At Risk ◽  
Small Molecular Weight ◽  
Calcium Dependent

The abundantly expressed small molecular weight proteins, CRYAB and HSPB2, have been implicated in cardioprotection ex vivo. However, the biological roles of CRYAB/HSPB2 coexpression for either ischemic preconditioning and/or protection in situ remain poorly defined. Wild-type (WT) and age-matched (∼5–9 mo) CRYAB/HSPB2 double knockout (DKO) mice were subjected either to 30 min of coronary occlusion and 24 h of reperfusion in situ or preconditioned with a 4-min coronary occlusion/4-min reperfusion × 6, before similar ischemic challenge (ischemic preconditioning). Additionally, WT and DKO mice were subjected to 30 min of global ischemia in isolated hearts ex vivo. All experimental groups were assessed for area at risk and infarct size. Mitochondrial respiration was analyzed in isolated permeabilized cardiac skinned fibers. As a result, DKO mice modestly altered heat shock protein expression. Surprisingly, infarct size in situ was reduced by 35% in hearts of DKO compared with WT mice (38.8 ± 17.9 vs. 59.8 ± 10.6% area at risk, P < 0.05). In DKO mice, ischemic preconditioning was additive to its infarct-sparing phenotype. Similarly, infarct size after ischemia and reperfusion ex vivo was decreased and the production of superoxide and creatine kinase release was decreased in DKO compared with WT mice ( P < 0.05). In permeabilized fibers, ADP-stimulated respiration rates were modestly reduced and calcium-dependent ATP synthesis was abrogated in DKO compared with WT mice. In conclusion, contrary to expectation, our findings demonstrate that CRYAB and HSPB2 deficiency induces profound adaptations that are related to 1) a reduction in calcium-dependent metabolism/respiration, including ATP production, and 2) decreased superoxide production during reperfusion. We discuss the implications of these disparate results in the context of phenotypic responses reported for CRYAB/HSPB2-deficient mice to different ischemic challenges.

Activated platelets contribute importantly to myocardial reperfusion injury

2006 ◽  
Vol 290 (2) ◽  
pp. H692-H699 ◽  
Author(s):  
Yaqin Xu ◽  
Yuqing Huo ◽  
Marie-Claire Toufektsian ◽  
Susan I. Ramos ◽  
Yongguang Ma ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Knockout Mice ◽  
Platelet Rich Plasma ◽  
Ischemia Reperfusion ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Wild Type ◽  
Platelet Poor Plasma ◽  
Activated Platelets

Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice ( P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment ( P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.

scholarly journals α-1-Adrenergic Receptor Agonist Activity of Clinical α-Adrenergic Receptor Agonists Interferes with α-2-Mediated Analgesia

2009 ◽  
Vol 110 (2) ◽  
pp. 401-407 ◽  
Author(s):  
Daniel W. Gil ◽  
Cynthia V. Cheevers ◽  
Karen M. Kedzie ◽  
Cynthia A. Manlapaz ◽  
Sandhya Rao ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Intraperitoneal Administration ◽  
Analgesic Efficacy ◽  
Therapeutic Window ◽  
Receptor Subtypes ◽  
Agonist Activity ◽  
Wild Type

Background The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects. Methods Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays. Results Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold. Conclusions Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.

Targeted deletion of A3 adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium

2001 ◽  
Vol 281 (4) ◽  
pp. H1751-H1758 ◽  
Author(s):  
Rachael J. Cerniway ◽  
Zequan Yang ◽  
Marlene A. Jacobson ◽  
Joel Linden ◽  
G. Paul Matherne
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Functional Recovery ◽  
Adenosine Receptors ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Tissue Viability ◽  
Targeted Deletion

A3 adenosine receptors (A3ARs) have been implicated in regulating mast cell function and in cardioprotection during ischemia-reperfusion injury. The physiological role of A3ARs is unclear due to the lack of widely available selective antagonists. Therefore, we examined mice with targeted gene deletion of the A3AR together with pharmacological studies to determine the role of A3ARs in myocardial ischemia-reperfusion injury. We evaluated the functional response to 15-min global ischemia and 30-min reperfusion in isovolumic Langendorff hearts from A3AR−/−and wild-type (A3AR+/+) mice. Loss of contractile function during ischemia was unchanged, but recovery of developed pressure in hearts after reperfusion was improved in A3AR−/− compared with wild-type hearts (80 ± 3 vs. 51 ± 3% at 30 min). Tissue viability assessed by efflux of lactate dehydrogenase was also improved in A3AR−/− hearts (4.5 ± 1 vs. 7.5 ± 1 U/g). The adenosine receptor antagonist BW-A1433 (50 μM) decreased functional recovery following ischemia in A3AR−/− but not in wild-type hearts. We also examined myocardial infarct size using an intact model with 30-min left anterior descending coronary artery occlusion and 24-h reperfusion. Infarct size was reduced by over 60% in A3AR−/− hearts. In summary, targeted deletion of the A3AR improved functional recovery and tissue viability during reperfusion following ischemia. These data suggest that activation of A3ARs contributes to myocardial injury in this setting in the rodent. Since A3ARs are thought to be present on resident mast cells in the rodent myocardium, we speculate that A3ARs may have proinflammatory actions that mediate the deleterious effects of A3AR activation during ischemia-reperfusion injury.

scholarly journals Enlarged Infarcts in Endothelial Nitric Oxide Synthase Knockout Mice are Attenuated by Nitro-L-Arginine

1996 ◽  
Vol 16 (5) ◽  
pp. 981-987 ◽  
Author(s):  
Zhihong Huang ◽  
Paul L. Huang ◽  
Jianya Ma ◽  
Wei Meng ◽  
Cenk Ayata ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Infarct Size ◽  
Knockout Mice ◽  
Endothelial Nitric Oxide Synthase ◽  
Type Strain ◽  
Wild Type Strain ◽  
Mutant Mice ◽  
Wild Type ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Infarct size and vascular hemodynamics were measured 24 h after middle cerebral artery (MCA) occlusion in mice genetically deficient in the endothelial nitric oxide synthase (eNOS) isoform. eNOS mutant mice developed larger infarcts (21%) than the wild-type strain when assessed 24 h after intraluminal filament occlusion. Moreover, regional CBF values recorded in the MCA territory by laser-Doppler flowmetry were more severely reduced after occlusion and were disproportionately reduced during controlled hemorrhagic hypotension in autoregulation experiments. Unlike the situation in wild-type mice, nitro-L-arginine superfusion (1 m M) dilated pial arterioles of eNOS knockout mice in a closed cranial window preparation. As noted previously, eNOS mutant mice were hypertensive. However, infarct size remained increased despite lowering blood pressure to normotensive levels by hydralazine treatment. Systemic administration of nitro-L-arginine decreased infarct size in eNOS mutant mice (24%) but not in the wild-type strain. This finding complements published data showing that nitro-L-arginine increases infarct size in knockout mice expressing the eNOS but not the neuronal NOS isoform (i.e., neuronal NOS knockout mice). We conclude that NO production within endothelium may protect brain tissue, perhaps by hemodynamic mechanisms, whereas neuronal NO overproduction may lead to neurotoxicity.

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